Clinical and Translational Imaging

, Volume 6, Issue 2, pp 113–121 | Cite as

Pretargeting in the context of theranostics and companion diagnostics in nuclear oncology

Mini Review
Part of the following topical collections:
  1. Radiochemistry and radiopharmacology

Abstract

Purpose

The concept of theranostics is well illustrated in nuclear oncology by radioactive iodide in thyroid diseases and by peptides or small molecular weight inhibitors in various cancers. It is also illustrated by radiolabeled antibodies, such as Zevalin, but radiolabeled antibodies have limitations that prompted the design of pretargeting. This review illustrates the achievements of pretargeting and focuses on its applications as theranostics or companion diagnostics.

Method

The review does not aim at exhaustivity. Examples from the already long history of pretargeting are selected to depict achievements but also outstanding issues.

Results

The idea of pretargeting, which separates antigen-binding from radionuclides, was proposed in the mid 1980s. Using avidin–biotin or bispecific antibodies and bivalent haptens, high contrast images and therapeutic efficacy were demonstrated in the clinic. However, the immunogenicity of streptavidin could not be abrogated, producing recombinant bispecific antibodies proved difficult and balancing between high tumor uptake and fast clearance of activity from normal tissues remains a challenge. These are the reasons for the continuing search for new approaches and new reagents. Some of these new approaches, particularly those based on biorthogonal chemistry or complementary oligonucleotides, are described and their potential as theranostics or companion diagnostics are discussed.

Conclusion

The future of pretargeting remains uncertain, because clinical development is complex and cost of goods is high. However, pretargeting as a theranostic tool is clinical relevant, especially with short half-life radionuclides for PET imaging or targeted alpha-radionuclide therapy.

Keywords

Molecular imaging Targeted radionuclide therapy Theranostics Companion diagnostics Antibodies Pretargeting 

Notes

Acknowledgements

This work was funded in part by grants of the French National Agency for Research within the “Investissements d’Avenir” program: Equipex ArronaxPlus (ANR-11-EQPX-0004) and Labex IRON (ANR-11-LABX-0018). The authors thank D.M. Goldenberg (Immunomedics, Inc., Morris Plains, NJ, USA) for continuous support.

Compliance with ethical standards

Conflict of interest

Jacques Barbet is a founding shareholder of Atlab Pharma SAS and OGD2 Pharma SAS, Nantes, France, companies that pursue the development of therapeutic antibodies.

Ethical standards statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

References

  1. 1.
    Robbins RJ, Schlumberger MJ (2005) The evolving role of 131I for the treatment of differentiated thyroid carcinoma. J Nucl Med 46(Suppl 1):28S–37SPubMedGoogle Scholar
  2. 2.
    Baum RP, Kulkarni HR, Carreras C (2012) Peptides and receptors in image-guided therapy: theranostics for neuroendocrine neoplasms. Semin Nucl Med 42:190–207.  https://doi.org/10.1053/j.semnuclmed.2012.01.002 CrossRefPubMedGoogle Scholar
  3. 3.
    Lütje S, Heskamp S, Cornelissen AS, Poeppel TD, van den Broek SA, Rosenbaum-Krumme S, Bockisch A, Gotthardt M, Rijpkema M, Boerman OC (2015) PSMA ligands for radionuclide imaging and therapy of prostate cancer: clinical status. Theranostics 5:1388–1401.  https://doi.org/10.7150/thno.13348.eCollection2015 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Buck AK, Stolzenburg A, Hänscheid H, Schirbel A, Lückerath K, Schottelius M, Wester HJ, Lapa C (2017) Chemokine receptor—directed imaging and therapy. Methods 130:63–71.  https://doi.org/10.1016/j.ymeth.2017.09.002 CrossRefPubMedGoogle Scholar
  5. 5.
    Dillman RO (2006) Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies. Clin Exp Med 6:1–12CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Goodwin DA, Meares CF, McCall MJ, McTigue M, Chaovapong W (1988) Pre-targeted immunoscintigraphy of murine tumors with indium-111-labeled bifunctional haptens. J Nucl Med 29(2):226–234PubMedGoogle Scholar
  7. 7.
    Goldenberg DM, Sharkey RM, Paganelli G, Barbet J, Chatal JF (2006) Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J Clin Oncol 24:823–834CrossRefPubMedGoogle Scholar
  8. 8.
    Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, Frampas E, Faivre-Chauvet A, Rauscher A, Sharkey RM, Goldenberg DM, Chatal JF, Barbet J (2015) A pretargeting system for tumor PET imaging and radioimmunotherapy. Front Pharmacol 6:54.  https://doi.org/10.3389/fphar.2015.00054.eCollection2015 PubMedPubMedCentralGoogle Scholar
  9. 9.
    Chatal JF, Campion L, Kraeber-Bodéré F, Bardet S, Vuillez JP, Charbonnel B, Rohmer V, Chang CH, Sharkey RM, Goldenberg DM, Barbet J, French Endocrine Tumor Group (2006) Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol 24:1705–1711CrossRefPubMedGoogle Scholar
  10. 10.
    Bailly C, Bodet-Milin C, Rousseau C, Faivre-Chauvet A, Kraeber-Bodéré F, Barbet J (2017) Pretargeting for imaging and therapy in oncological nuclear medicine. EJNMMI Radiopharm Chem 2:6.  https://doi.org/10.1186/s41181-017-0026-8 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Herrmann K, Bluemel C, Weineisen M, Schottelius M, Wester HJ, Czernin J, Eberlein U, Beykan S, Lapa C, Riedmiller H, Krebs M, Kropf S, Schirbel A, Buck AK, Lassmann M (2015) Biodistribution and radiation dosimetry for a probe targeting prostate-specific membrane antigen for imaging and therapy. J Nucl Med 56:855–861.  https://doi.org/10.2967/jnumed.115.156133 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Jacene HA, Filice R, Kasecamp W, Wahl RL (2009) 18F-FDG PET/CT for monitoring the response of lymphoma to radioimmunotherapy. J Nucl Med 50:8–17.  https://doi.org/10.2967/jnumed.108.055376 CrossRefPubMedGoogle Scholar
  13. 13.
    Tagawa ST, Milowsky MI, Morris M, Vallabhajosula S, Christos P, Akhtar NH, Osborne J, Goldsmith SJ, Larson S, Taskar NP, Scher HI, Bander NH, Nanus DM (2013) Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res 19:5182–5191.  https://doi.org/10.1158/1078-0432.CCR-13-0231 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jauw YW, Menke-van der Houven van Oordt CW, Hoekstra OS, Hendrikse NH, Vugts DJ, Zijlstra JM, Huisman MC, van Dongen GA (2016) Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: what Can We Learn from Initial Clinical Trials? Front Pharmacol 7:131.  https://doi.org/10.3389/fphar.2016.00131.eCollection2016 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jain M, Venkatraman G, Batra SK (2007) Optimization of radioimmunotherapy of solid tumors: biological impediments and their modulation. Clin Cancer Res 13:1374–1382CrossRefPubMedGoogle Scholar
  16. 16.
    Stickney DR, Anderson LD, Slater JB, Ahlem CN, Kirk GA, Schweighardt SA, Frincke JM (1991) Bifunctional antibody: a binary radiopharmaceutical delivery system for imaging colorectal carcinoma. Cancer Res 51:6650–6655PubMedGoogle Scholar
  17. 17.
    Goldenberg DM, Chang CH, Rossi EA, McBride JW, Sharkey RM (2012) Pretargeted molecular imaging and radioimmunotherapy. Theranostics 2:523–540.  https://doi.org/10.7150/thno.3582 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Breitz HB, Weiden PL, Beaumier PL, Axworthy DB, Seiler C, Su FM, Graves S, Bryan K, Reno JM (2000) Clinical optimization of pretargeted radioimmunotherapy with antibody-streptavidin conjugate and 90Y-DOTA-biotin. J Nucl Med 41:131–140PubMedGoogle Scholar
  19. 19.
    Paganelli G, Magnani P, Zito F, Villa E, Sudati F, Rossetti C, Fazio F (1991) Three-step monoclonal antibody tumor targeting in carcinoembryonic antigen positive patients. Cancer Res 51:5960–5966PubMedGoogle Scholar
  20. 20.
    Dosio F, Magnani P, Paganelli G, Samuel A, Chiesa G, Fazio F (1993) Three-step tumor pre-targeting in lung cancer immunoscintigraphy. J Nucl Biol Med 37:228–232PubMedGoogle Scholar
  21. 21.
    Paganelli G, Grana C, Chinol M, Cremonesi M, De Cicco C, De Braud F, Robertson C, Zurrida S, Casadio C, Zoboli S, Siccardi AG, Veronesi U (1999) Antibody-guided three-step therapy for high grade glioma with yttrium-90 biotin. Eur J Nucl Med 26:348–357CrossRefPubMedGoogle Scholar
  22. 22.
    Grana C, Chinol M, Robertson C, Mazzetta C, Bartolomei M, De Cicco C, Fiorenza M, Gatti M, Caliceti P, Paganelli G (2002) Pretargeted adjuvant radioimmunotherapy with yttrium-90-biotin in malignant glioma patients: a pilot study. Br J Cancer 86:207–212CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    van Rij CM, Lütje S, Frielink C, Sharkey RM, Goldenberg DM, Franssen GM, McBride WJ, Rossi EA, Oyen WJ, Boerman OC (2013) Pretargeted immuno-PET and radioimmunotherapy of prostate cancer with an anti-TROP-2 × anti-HSG bispecific antibody. Eur J Nucl Med Mol Imaging 40:1377–1383.  https://doi.org/10.1007/s00259-013-2434-7 CrossRefPubMedGoogle Scholar
  24. 24.
    Keinänen O, Fung K, Pourat J, Jallinoja V, Vivier D, Pillarsetty NK, Airaksinen AJ, Lewis JS, Zeglis BM, Sarparanta M (2017) Pretargeting of internalizing trastuzumab and cetuximab with a 18F-tetrazine tracer in xenograft models. EJNMMI Res 7:95.  https://doi.org/10.1186/s13550-017-0344-6 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Le Doussal JM, Gruaz-Guyon A, Martin M, Gautherot E, Delaage M, Barbet J (1990) Targeting of indium 111-labeled bivalent hapten to human melanoma mediated by bispecific monoclonal antibody conjugates: imaging of tumors hosted in nude mice. Cancer Res 50:3445–3452PubMedGoogle Scholar
  26. 26.
    Boerman OC, Kranenborg MH, Oosterwijk E, Griffiths GL, McBride WJ, Oyen WJ, de Weijert M, Oosterwijk-Wakka J, Hansen HJ, Corstens FH (1999) Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate. Cancer Res 59:4400–4405PubMedGoogle Scholar
  27. 27.
    Barbet J, Peltier P, Bardet S, Vuillez JP, Bachelot I, Denet S, Olivier P, Leccia F, Corcuff B, Huglo D, Proye C, Rouvier E, Meyer P, Chatal JF (1998) Radioimmunodetection of medullary thyroid carcinoma using indium-111 bivalent hapten and anti-CEA × anti-DTPA-indium bispecific antibody. J Nucl Med 39:1172–1178PubMedGoogle Scholar
  28. 28.
    Gautherot E, Rouvier E, Daniel L, Loucif E, Bouhou J, Manetti C, Martin M, Le Doussal JM, Barbet J (2000) Pretargeted radioimmunotherapy of human colorectal xenografts with bispecific antibody and 131I-labeled bivalent hapten. J Nucl Med 41:480–487PubMedGoogle Scholar
  29. 29.
    Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, Ferrer L, Faivre-Chauvet A, Campion L, Vuillez JP, Devillers A, Chang CH, Goldenberg DM, Chatal JF, Barbet J (2006) Targeting, toxicity, and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131I-labeled bivalent hapten in a phase I optimization clinical trial. J Nucl Med 47:247–255PubMedGoogle Scholar
  30. 30.
    Rossi EA, Chang CH, Losman MJ, Sharkey RM, Karacay H, McBride W, Cardillo TM, Hansen HJ, Qu Z, Horak ID, Goldenberg DM (2005) Pretargeting of carcinoembryonic antigen-expressing cancers with a trivalent bispecific fusion protein produced in myeloma cells. Clin Cancer Res 11:7122s–7129sCrossRefPubMedGoogle Scholar
  31. 31.
    Rossi EA, Goldenberg DM, Cardillo TM, McBride WJ, Sharkey RM, Chang CH (2006) Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting. Proc Natl Acad Sci USA 103:6841–6846CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sharkey RM, Rossi EA, McBride WJ, Chang CH, Goldenberg DM (2010) Recombinant bispecific monoclonal antibodies prepared by the dock-and-lock strategy for pretargeted radioimmunotherapy. Semin Nucl Med 40:190–203.  https://doi.org/10.1053/j.semnuclmed.2009.12.002 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sharkey RM, McBride WJ, Karacay H, Chang K, Griffiths GL, Hansen HJ, Goldenberg DM (2003) A universal pretargeting system for cancer detection and therapy using bispecific antibody. Cancer Res 63:354–363PubMedGoogle Scholar
  34. 34.
    Goldenberg DM, Rossi EA, Sharkey RM, McBride WJ, Chang CH (2008) Multifunctional antibodies by the Dock-and-Lock method for improved cancer imaging and therapy by pretargeting. J Nucl Med 49:158–163CrossRefPubMedGoogle Scholar
  35. 35.
    Schoffelen R, Sharkey RM, Goldenberg DM, Franssen G, McBride WJ, Rossi EA, Chang CH, Laverman P, Disselhorst JA, Eek A, van der Graaf WT, Oyen WJ, Boerman OC (2010) Pretargeted immuno-positron emission tomography imaging of carcinoembryonic antigen-expressing tumors with a bispecific antibody and a 68Ga- and 18F-labeled hapten peptide in mice with human tumor xenografts. Mol Cancer Ther 9:1019–1027.  https://doi.org/10.1158/1535-7163.mct-09-0862 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Bodet-Milin C, Faivre-Chauvet A, Carlier T, Rauscher A, Bourgeois M, Cerato E, Rohmer V, Couturier O, Drui D, Goldenberg DM, Sharkey RM, Barbet J, Kraeber-Bodere F (2016) Immuno-PET using anticarcinoembryonic antigen bispecific antibody and 68 Ga-labeled peptide in metastatic medullary thyroid carcinoma: clinical optimization of the pretargeting parameters in a first-in-human trial. J Nucl Med 57:1505–1511CrossRefPubMedGoogle Scholar
  37. 37.
    Schoffelen R, Boerman OC, Goldenberg DM, Sharkey RM, van Herpen CM, Franssen GM, McBride WJ, Chang CH, Rossi EA, van der Graaf WT, Oyen WJ (2013) Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results. Br J Cancer 109:934–942.  https://doi.org/10.1038/bjc.2013.376 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bodet-Milin C, Ferrer L, Rauscher A, Masson D, Rbah-Vidal L, Faivre-Chauvet A, Cerato E, Rousseau C, Hureaux J, Couturier O, Salaün PY, Goldenberg DM, Sharkey RM, Kraeber-Bodéré F, Barbet J (2015) Pharmacokinetics and dosimetry studies for optimization of pretargeted radioimmunotherapy in CEA-expressing advanced lung cancer patients. Front Med (Lausanne) 2:84Google Scholar
  39. 39.
    Schoffelen R, Woliner-van der Weg W, Visser EP, Goldenberg DM, Sharkey RM, McBride WJ, Chang CH, Rossi EA, van der Graaf WT, Oyen WJ, Boerman OC (2014) Predictive patient-specific dosimetry and individualized dosing of pretargeted radioimmunotherapy in patients with advanced colorectal cancer. Eur J Nucl Med Mol Imaging 41:1593–1602.  https://doi.org/10.1007/s00259-014-2742-6 PubMedGoogle Scholar
  40. 40.
    Bos ES, Kuijpers WH, Meesters-Winters M, Pham DT, de Haan AS, van Doornmalen AM, Kaspersen FM, van Boeckel CA, Gougeon-Bertrand F (1994) In vitro evaluation of DNA-DNA hybridization as a two-step approach in radioimmunotherapy of cancer. Cancer Res 54:3479–3486PubMedGoogle Scholar
  41. 41.
    Liu G, Mang’era K, Liu N, Gupta S, Rusckowski M, Hnatowich DJ (2002) Tumor pretargeting in mice using 99mTc-labeled morpholino, a DNA analog. J Nucl Med 43:384–391PubMedGoogle Scholar
  42. 42.
    Schubert M, Bergmann R, Förster C, Sihver W, Vonhoff S, Klussmann S, Bethge L, Walther M, Schlesinger J, Pietzsch J, Steinbach J, Pietzsch HJ (2017) Novel tumor pretargeting system based on complementary l-configured oligonucleotides. Bioconjug Chem 28:1176–1188.  https://doi.org/10.1021/acs.bioconjchem.7b00045 CrossRefPubMedGoogle Scholar
  43. 43.
    Rossin R, Verkerk PR, van den Bosch SM, Vulders RC, Verel I, Lub J, Robillard MS (2010) In vivo chemistry for pretargeted tumor imaging in live mice. Angew Chem Int Ed Engl 49:3375–3378.  https://doi.org/10.1002/anie.200906294 CrossRefPubMedGoogle Scholar
  44. 44.
    Zeglis BM, Sevak KK, Reiner T, Mohindra P, Carlin SD, Zanzonico P, Weissleder R, Lewis JS (2013) A pretargeted PET imaging strategy based on bioorthogonal Diels–Alder click chemistry. J Nucl Med 54:1389–1396.  https://doi.org/10.2967/jnumed CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Baskin JM, Prescher JA, Laughlin ST, Agard NJ, Chang PV, Miller IA, Lo A, Codelli JA, Bertozzi CR (2007) Copper-free click chemistry for dynamic in vivo imaging. Proc Natl Acad Sci USA 104:16793–16797CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rossin R, Läppchen T, van den Bosch SM, Laforest R, Robillard MS (2013) Diels–Alder reaction for tumor pretargeting: in vivo chemistry can boost tumor radiation dose compared with directly labeled antibody. J Nucl Med 54:1989–1995.  https://doi.org/10.2967/jnumed.113.123745 CrossRefPubMedGoogle Scholar
  47. 47.
    Houghton JL, Membreno R, Abdel-Atti D, Cunanan KM, Carlin S, Scholz WW, Zanzonico PB, Lewis JS, Zeglis BM (2017) Establishment of the in vivo efficacy of pretargeted radioimmunotherapy utilizing inverse electron demand Diels–Alder Click Chemistry. Mol Cancer Ther 16:124–133.  https://doi.org/10.1158/1535-7163.MCT-16-0503 CrossRefPubMedGoogle Scholar
  48. 48.
    van Duijnhoven SM, Rossin R, van den Bosch SM, Wheatcroft MP, Hudson PJ, Robillard MS (2015) Diabody pretargeting with click chemistry in vivo. J Nucl Med 56:1422–1428.  https://doi.org/10.2967/jnumed.115.159145 CrossRefPubMedGoogle Scholar
  49. 49.
    Altai M, Perols A, Tsourma M, Mitran B, Honarvar H, Robillard M, Rossin R, ten Hoeve W, Lubberink M, Orlova A, Karlström AE, Tolmachev V (2016) Feasibility of affibody-based bioorthogonal chemistry-mediated radionuclide pretargeting. J Nucl Med 57:431–436.  https://doi.org/10.2967/jnumed.115.162248 CrossRefPubMedGoogle Scholar
  50. 50.
    Honarvar H, Westerlund K, Altai M, Sandström M, Orlova A, Tolmachev V, Karlström AE (2016) Feasibility of affibody molecule-based PNA-mediated radionuclide pretargeting of malignant tumors. Theranostics 6:93–103.  https://doi.org/10.7150/thno.12766 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Westerlund K, Altai M, Mitran B, Konijnenberg M, Oroujeni M, Atterby C, de Jong M, Orlova A, Mattsson J, Micke P, Eriksson Karlström A, Tolmachev V (2018) Radionuclide therapy of HER2-expressing human xenografts using an affibody molecule-based PNA-mediated pretargeting: in vivo proof-of-principle. J Nucl Med.  https://doi.org/10.2967/jnumed.118.208348 PubMedGoogle Scholar
  52. 52.
    Jurcic JG, Rosenblat TL (2014) Targeted alpha-particle immunotherapy for acute myeloid leukemia. Am Soc Clin Oncol Educ Book. https://doi.org/10.14694/edbook_am.2014.34.e126Google Scholar
  53. 53.
    Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, Kopka K, Apostolidis C, Haberkorn U, Morgenstern A (2016) 225Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med 57:1941–1944CrossRefPubMedGoogle Scholar
  54. 54.
    Heskamp S, Hernandez R, Molkenboer-Kuenen JDM, Essler M, Bruchertseifer F, Morgenstern A, Steenbergen EJ, Cai W, Seidl C, McBride WJ, Goldenberg DM, Boerman OC (2017) α-Versus β-emitting radionuclides for pretargeted radioimmunotherapy of carcinoembryonic antigen-expressing human colon cancer xenografts. J Nucl Med 58:926–933.  https://doi.org/10.2967/jnumed.116.187021 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Green DJ, O’Steen S, Lin Y, Comstock ML, Kenoyer AL, Hamlin DK, Wilbur DS, Fisher DR, Nartea M, Hylarides MD, Gopal AK, Gooley TA, Orozco JJ, Till BG, Orcutt KD, Wittrup KD, Press OW (2018) CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies. Blood 131:611–620.  https://doi.org/10.1182/blood-2017-09-807610 CrossRefPubMedGoogle Scholar
  56. 56.
    Shah MA, Zhang X, Rossin R, Robillard MS, Fisher DR, Bueltmann T, Hoeben FJM, Quinn TP (2017) Metal-free cycloaddition chemistry driven pretargeted radioimmunotherapy using α-particle radiation. Bioconjug Chem 28:3007–3015.  https://doi.org/10.1021/acs.bioconjchem.7b00612 CrossRefPubMedGoogle Scholar

Copyright information

© Italian Association of Nuclear Medicine and Molecular Imaging 2018

Authors and Affiliations

  1. 1.GIP ArronaxSaint-Herblain CedexFrance

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